5-Methyl-isoxazole-4-carboxylic acid anilides

ABSTRACT

A 5-methyl-isoxazole-4-carboxylic acid anilide is prepared by heating an acetoacetic acid anilide with an orthoformic acid ester and a carboxylic acid anhydride, isolating the resulting 2-alkoxymethylene-acetoacetic acid anilide and then treating it with hydroxylamine in an organic solvent. The compounds of the invention have anti-inflammatory and analgetic activity.

The present invention relates to 5-methyl-isoxazole-4-carboxylic acidanilides of the formula I ##STR1## in which R₁, R₂ and R₃, which may beidentical or different, each stand for an alkyl group of 1, 2 or 3carbon atoms, an alkoxy group of 1, 2 or 3 carbon atoms, an alkylthiogroup of 1, 2 or 3 carbon atoms, which groups may be substituted partlyor totally by identical or different halogen atoms, such as fluorine,chlorine, bromine or iodine atoms; for halogen atoms, such as fluorine,chlorine, bromine or iodine atoms, for nitro, cyano, alkoxycarbonylgroups of 1, 2 or 3 carbon atoms in the alkyl moiety, and in which R₁and R₂ each further stands for hydrogen, in which case, however, R₃cannot stand for methyl but additionally can stand for a phenyl groupwhich may carry one or two fluorine, chlorine, bromine or iodine atoms,alkyl groups of 1, 2 or 3 carbon atoms or alkoxy groups of 1, 2 or 3carbon atoms, or for a phenoxy group which may carry one or twofluorine, chlorine, bromine or iodine atoms, alkyl groups of 1, 2 or 3carbon atoms or alkoxy groups of 1, 2 or 3 carbon atoms, or in which R₁stands for hydrogen, and R₂ and R₃ together stand for a methylene-dioxygroup or together with the phenyl ring, to which they are linked, theystand for a naphthalene ring.

Preferred are compounds of formula I, in which R₁ and R₂ each stands forhydrogen, R₃ for halogen, such as a fluorine, chlorine, or bromine atom,the CF₃ -group, an alkoxy group of 1 or 2 carbon atoms which may besubstituted partly or entirely by identical or different halogen atoms,especially by fluorine or chlorine atoms.

Furthermore preferred are compounds of formula I in which R₁ stands forhydrogen, R₂ and R₃, which may be identical or different, each stand forhalogen, such as a chlorine, fluorine or bromine atom, or the CF₃-group.

Still further preferred are compounds of formula I, in which R₁ standsfor hydrogen, R₂ for an alkyl group of 1 or 2 carbon atoms and R₃ for ahalogen atom, such as a fluorine, chlorine or bromine atom.

More specifically preferred is a compound of the formula I, in which R₁stands for hydrogen, and R₂ and R₃ together form the 3,4-methylene-dioxygroup.

The present invention further relates to a process for the manufactureof the compounds of formula I, which comprises heating an acetoaceticacid anilide of the formula II ##STR2## in which R₁, R₂ and R₃ have themeaning given above, with an advantageously at least equimolar amount ofan orthoformic acid ester of the formula III

    hc(or).sub.3                                               (iii)

in which R stands for an alkyl group of 1 to 4 carbon atoms, preferablymethyl or ethyl, and advantageously with a 2- to 4-fold molar excessamount of a carboxylic acid anhydride, advantageously an aliphaticcarboxylic acid anhydride having 2 to 6 carbon atoms, preferably aceticanhydride, for 30 minutes to 3 hours to a temperature of from 80° to150° C, preferably to the boiling point of the mixture, isolating theresulting 2-alkoxymethylene-acetoacetic acid anilide of the generalformula IV ##STR3## in which R, R₁, R₂ and R₃ have the meaning givenabove, and then treating this compound with an advantageously at leastequimolar amount of hydroxyamine in an organic solvent or mixture ofsolvents, preferably methanol, ethanol, propanol or isopropanol,optionally with the addition of up to 2 parts by volume, preferably upto 1 part by volume, of water per part by volume of organic solvent, ata temperature of from 0° to 100° C, preferably from 10° to 50° C.

The 2-alkoxymethylene-acetoacetic acid anilides of formula IV requiredfor the manufacture of the compounds of formula I as starting materialare new compounds.

Merely the preparation of the 2-ethoxymethylene-acetoacetic acidanilide, which is outside the scope of this invention, from acetoaceticacid anilide, orthoformic acid triethyl ester and acetic anhydride hasbeen described by G. Kempter, W. Schmidt and H. Dost, Chem. Ber. 98, 955to 961 (1965).

Table 1 comprises the new 2-ethoxymethylene-acetoacetic acid anilides.

The isoxazoles of formula I of this invention are new compounds. Merelythree analogues of the isoxazoles, in which R₁, R₂ and R₃ stand forhydrogen, or R₁ and R₂ stand for hydrogen and R₃ for 2-CH₃ or 4-CH₃,have been described by F. B. Dains and E. L. Griffin, J. Am. Chem. Soc.35, 959 to 976 (1913). Those known compounds, however, have nopractically useful anti-inflammatory or analgetic properties.

The reaction step starting from a compound of formula IV to yield thecompound of formula I is surprising. It comprises cyclisation of theeasily obtainable 2-ethoxymethylene-acetoacetic acid anilides withhydroxylamine to provide the isoxazoles of formula I already at roomtemperature with a yield of from 90 to 100%.

The new compounds of formula I are listed in Table 2.

The compounds of formula I of the invention exhibit stronganti-inflammatory and analgetic properties. Having about the sameanti-inflammatory effect, they have substantially lower toxicity levelsthan the known phenylbutazone, or at about the same toxicity level theyexhibit a better activity.

Moreover, their analgetic effect is superior to that of phenylbutazone,and their ulcerogenic side effect is substantially weaker than that ofphenylbutazone.

Their anti-inflammatory effect was demonstrated on adjuvant arthritis inrats (Pearson, C. M. and Wood, F. D., Arthrit. Rheumat., 2 (1959), 440)and their analgetic effect was demonstrated by means of the writhingtest in mice (Sigmund, E. et al., Proc. Soc. Exp. Biol. Med. 95 (1957),729).

The ED₅₀ levels were determined graphically on probability paper. In thewrithing test, the ED₅₀ is defined to be the dose of active ingredientthat reduces the number of writhings by 50% as compared to a controlgroup. In the adjuvant arthritis test, the effect was judged byobserving the inhibition in the secondary lesions, which the animalsinflicted to their ears, paws and tails, on the 17th day afteradministration of the active ingredient compositions had started, incomparison with the control group. ED₅₀ is considered the dose thatreduces these lesions by 50% as compared to those of the control group.

To examine the ulcerogenic activity, the substances to be tested wereorally administered to male rats of a Sprague-Dawley strain that hadbeen kept unfed for 18 hours. 24 hours after administration, thegastrointestinal tract of the animals was inspected for ulcers.

In a test for the acute toxicity according to Litchfield and Wilcoxon(Litchfield, J. T. And Wilcoxon, F. W., J. Pharmacol. exp. Ther. 96(1949), 99), the LD₅₀ levels were determined in male or female N.M.R.I.mice or in female Wister-Lewis rats.

The data found for some compounds of formula I and for the knownphenylbutazone are listed in the following Table 3.

                                      TABLE 3                                     __________________________________________________________________________    Substance                                                                           ED.sub.50 in mg/kg per os                                                               LD.sub.50 in mg/kg per os.sup.1)                                                           Limit dose in mg/kg                              No. from                                                                            writhing                                                                           adjuvant          per os without ulcero-                           Table 2                                                                             test arthritis                                                                            mice rats  genic activity                                   __________________________________________________________________________    6     <60   24    1280   920 100                                                              (780 - 2099)                                                                         826 - 1025)                                            12    25 - 40                                                                             42    2530   -   --                                                               (2162 - 2960)                                                 8     ca. 60                                                                             <100   2330  >3150                                                                              ≧400                                                      (1752 - 3099)                                                 21    <60  <100  300 - 100.sup.2)                                                                      --  --                                               Phenyl-                                                                             60 - 100                                                                            37    1145   780  63                                              butazone        (939-1397)                                                                           (675 - 901)                                            __________________________________________________________________________     .sup.1) Limits of confidence for p = 0.05 in brackets Observation time 7      days                                                                          .sup.2) administered by the intraperitoneal route                        

The following Examples illustrate the invention.

EXAMPLE 1:

(a) 2-Ethoxymethylene-acetoacetic acid-3,4-dichloro-anilide of formulaIV

1.0 Mol of acetoacetic acid-3,4-dichloro-anilide of formula II (246 g)is refluxed with 1.12 mols of orthoformic acid triethyl ester of formulaIII (166 g) and 2.97 mols of acetic anhydride (302 g) for 1.5 hours.After cooling to room temperature, the precipitated crystals aresuction-filtered and washed with a mixture of 1 part by volume ofbenzene and 2 parts by volume of gasoline. The yield amounts to 251 g,corresponding to 83% of the theoretical yield of2-ethoxymethylene-acetoacetic acid-3,4-dichloro-anilide. Melting pointafter recrystallization from benzene: 125° to 126° C.

C₁₃ H₁₃ Cl₂ No₃ molecular weight 302.15 Calculated: C 51.7%; H 4.3%; N4.6% Found: C 51.8%; H 4.1%; N 4.5%

In an analogous manner, the compounds listed in Table 1 were prepared.In the case of readily soluble 2-ethoxymethylene-acetoacetic acidanilides, the reaction mixture must, under certain circumstances, beconcentrated by distillation.

(b) 5-Methyl-isoxazole-4-carboxylic acid-3,4-dichloro-anilide of formulaI

0.11 mol (7.65 g) of hydroxy-amine hydrochloride was dissolved in 30 mlof water, an ice-cold solution of 0.11 mol of sodium hydroxide (4.4 g)in 20 ml of water was added, and the mixture was diluted with 150 ml ofmethanol. Then, 0.1 mol (30.2 g) of the 2-ethoxymethyleneacetoaceticacid-3,4-dichloro-anilide obtained according to a) was added, and themixture was stirred for about 4 hours at room temperature. The solutionwas then cooled to +5° C, the crystals were suction-filtered and washedwith water. After drying in air, colorless crystals were obtained. Theyield amounted to 26.4 g, corresponding to 97.5% of the theoreticalyield of 5-methyl-isoxazole-4-carboxylic acid-3,4-dichloroanilide.Melting point after recrystallization from methanol: 146° C.

C₁₁ H₈ Cl₂ N₂ O₂ molecular weight 271.1 Calculated: C 48.7%; H 3.0%; N10.3% Found: C 48.6%; H 3.0%; N 10.2%

In an analogous manner, the compounds listed in Table 2 were prepared.

                  TABLE 1                                                         ______________________________________                                        Intermediate products of formula IV:                                          Nr.   R.sub.1 R.sub.2  R.sub.3      melting point                                                                 (° C)                              ______________________________________                                        1     H       H        2-Cl         95-96                                     2     H       H        3-Cl          98                                       3     H       H        4-Cl           139.5                                   4     H       2-Cl     4-Cl         127                                       5     H       2-Cl     5-Cl         146                                       6     H       3-Cl     4-Cl         125-126                                   7     H       3-Cl     5-Cl         131                                       8     H       H        3-Br         118                                       9     H       H        4-Br         124                                       10    H       H        4-F          127                                       11    H       H        3-CF.sub.3    84                                       12    H       3-CF.sub.3                                                                             5-CF.sub.3   111                                       13    H       H        4-NO.sub.2   160-162                                   14    H       H        3-OCF.sub.2CHF.sub.2                                                                       73-74                                     15    H       H        3-CH.sub.3    73                                       16    H       2-CH.sub.3                                                                             4-CH.sub.3   105                                       17    H       H        2-OCH.sub.3  94-95                                     18    H       H        3-OCH.sub.3   88                                       19    H       H        4-OCH.sub.3   94                                       20    H       H        2-OC.sub.2 H.sub.5                                                                         110                                       21    H                                                                                      ##STR4##           136-137                                     22    H       H        4-COOC.sub.2 H.sub.5                                                                       137-138                                   23     H                                                                                     ##STR5##           126                                         24    H       2-CH.sub.3                                                                             3-Cl         129                                       25    H       2-CH.sub.3                                                                             4-Cl         128                                       26    H       2-CH.sub.3                                                                             5-Cl         141                                       27    H       2-CF.sub.3                                                                             4-Cl         108                                       28    H       H                                                                                       ##STR6##    78-79                                     29    H       H                                                                                       ##STR7##     88                                       30    H       H                                                                                       ##STR8##    113-114                                   31    H       H        3-OCF.sub.2CHClF                                                                            62                                       32    H       H        3-SCH.sub.3   92                                       33    H       2-Br     5-Br         140                                       34    H       3-Cl     4-CH.sub.3   120                                       35    H       H        3-J          148                                       36    H       H        3-CN           106.5                                   37    H       2-CH.sub.3                                                                             5-Br         140-141                                   38    H       3-CH.sub.3                                                                             4-Br         123                                       39    H       H        3-F          109.5                                     40    H       2-CH.sub.3                                                                             3-F          124 - 125                                 41    H       3-Cl     4-F          110.5 - 111.5                             42    H       3-CF.sub.3                                                                             4-Cl         115.5                                     43    H       H        4-SCH.sub.3  116 - 118                                 44    2-OCH.sub.3                                                                           5-OCH.sub.3                                                                            4-Cl         154.5 - 156                               45    H       2-F      5-CF.sub.3   139.5 -  140                              46    2-F     4-F      5-Cl         138                                       47    H       H        I            148.5 - 149                               48    H       2-OCH.sub.3                                                                            4-OCH.sub.3  142 - 142.5                               49    H       2-OCH.sub.3                                                                            5-OCH.sub.3  116                                       ______________________________________                                    

                  table 2                                                         ______________________________________                                        5-methyl-isoxazole-4-carboxylic acid anilides of formula I                                                        melting                                   No.   R.sub.1 R.sub.2  R.sub.3      point (° C)                        ______________________________________                                        1     H       H        2-Cl         111-112                                   2     H       H        3-Cl         106-107                                   3     H       H        4-Cl         151                                       4     H       2-Cl     4-Cl         120-121                                   5     H       2-Cl     5-Cl         122                                       6     H       3-Cl     4-Cl         146                                       7     H       3-Cl     5-Cl         182-183                                   8     H       H        3-Br         122                                       9     H       H        4-Br         162-163                                   10    H       H        4-F          117-118                                   11    H       H        3-CF.sub.3   119-120                                   12    H       3-CF.sub.3                                                                             5-CF.sub.3   176                                       13    H       H        4-NO.sub.2   190-191                                   14    H       H        3-OCF.sub.2CHF.sub.2                                                                       <40                                       15    H       H        3-CH.sub.3   80-81                                     16    H       2-CH.sub.3                                                                             4-CH.sub.3   160-161                                   17    H       H        2-OCH.sub.3  81.5                                      18    H       H        3-OCH.sub.3  92-93                                     19    H       H        4-OCH.sub.3  133-134                                   20    H       H        2-OC.sub.2 H.sub.5                                                                         105-106                                   21    H                                                                                      ##STR9##           125-126                                     22    H       H        4-COOC.sub.2 H.sub.5                                                                       167.5                                     23    H                                                                                      ##STR10##          137-138                                     24    H       2-CH.sub.3                                                                             3-Cl         158-159                                   25    H       2-CH.sub.3                                                                             4-Cl         147-148                                   26    H       2-CH.sub.3                                                                             5-Cl         127-128                                   27    H       2-CF.sub.3                                                                             4-Cl         133-134                                   28    H       H                                                                                       ##STR11##   116-117                                   29    H       H                                                                                       ##STR12##   137-138                                   30    H       H                                                                                       ##STR13##   138                                       31    H       H        3-OCF.sub.2CHClF                                                                           73.5-74.5                                 32    H       H        3-SCH.sub.3  71-72                                     33    H       2-Br     5-Br         171-173                                   34    H       3-Cl     4-CH.sub.3   149-150                                   35    H       H        3-I          148-149                                   36    H       H        3-CN         199.5-200.5                               37    H       2-CH.sub.3                                                                             5-Br         138-139                                   38    H       3-CH.sub.3                                                                             4-Br         130-131                                   39    H       H        3-F          122                                       40    H       2-CH.sub.3                                                                             3-F          142                                       41    H       3-Cl     4-F          123 - 124                                 42    H       3-CF.sub.3                                                                             4-Cl         161 - 161.5                               43    H       H        4-SCH.sub.3  135.5 - 136.5                             44    2-OCH.sub.3                                                                           5-OCH.sub.3                                                                            4-Cl         136 - 137.5                               45    H       2-F      5-CF.sub.3   107 - 108                                 46    2-F     4-F      5-Cl         127                                       47    H       H        4-I          173 - 173.5                               48    H       2-OCH.sub.3                                                                            4-OCH.sub.3  133.5 - 134                               49    H       2-OCH.sub.3                                                                            5-OCH.sub.3  87.5 - 88                                 ______________________________________                                    

i claim:
 1. A 5-methyl-isoxazole-4-carboxylic acid anilide of theformula ##STR14## wherein (A) R₁ and R₂ are each hydrogen and R₃ ishalogen, --CF₃, alkoxy having 1 or 2 carbon atoms, or halo-substitutedalkoxy having 1 or 2 carbon atoms;(B) R₁ is hydrogen and R₂ and R₃,which are the same or different, are halogen or --CF₃ ; (c) r₁ ishydrogen, R₂ is alkyl having 1 or 2 carbon atoms, and R₃ is halogen; or(D) R₁ is hydrogen and R₂ and R₃ are 3',4'- methylene dioxy.
 2. Acompound as in claim 1 (A).
 3. A compound as in claim 1 (B).
 4. Acompound as in claim 1 (C).
 5. A compound as in claim 1 (D).
 6. Apharmaceutical composition comprising an effective amount of a compoundas in claim 1 in combination with a pharmaceutically acceptable carrier.7. The method of combatting pain and/or inflammation which comprisesadministering an effective amount of a compound as in claim 1 to apatient in need of such treatment.
 8. A compound as in claim 2 which is5-methyl-isoxazole-4-carboxylic acid 4-fluoroanilide.
 9. A compound asin claim 2 which is 5-methyl-isoxazole 4-carboxylic acid4-chloroanilide.
 10. A compound as in claim 2 which is5-methyl-isoxazole-4-carboxylic acid 4-bromoanilide.
 11. A compound asin claim 2 which is 5-methyl-isoxazole 4-carboxylic acid 4-iodoanilide.12. A compound as in claim 2 which is 5-methyl-isoxazole-4-carboxylicacid 3-trifluoromethylanilide.
 13. A compound as in claim 3 which is5-methyl-isoxazole-4-carboxylic acid 3,4-dichloroanilide.
 14. A compoundas in claim 3 which is 5-methyl-isoxazole-4-carboxylic acid3,5-bis-trifluoromethyl anilide.
 15. A compound as in claim 3 which is5-methyl-isoxazole-4-carboxylic acid 3- chloro-4-fluoroanilide.
 16. Acompound as in claim 3 which is 5-methyl-isoxazole-4-carboxylic acid3-trifluoromethyl-4-chloroanilide.
 17. A compound as in claim 3 which is5-methyl-isoxazole-4-carboxylic acid 2-fluoro-5-trifluoromethyl anilide.18. A compound as claim 4 which is 5-methyl-isoxazole-carboxylic acid2-methyl-3-chloroanilide.
 19. ##STR15##
 20. A pharmaceutical compositioncomprising an effective amount of the compound of claim 19 incombination with a pharmaceutically-acceptable carrier.
 21. The methodof combatting pain and/or inflammation which comprises administering aneffective amount of the compound of claim 19 to a patient in need ofsuch treatment.
 22. ##STR16##
 23. A pharmaceutical compositioncomprising an effective amount of the compound of claim 22 incombination with a pharmaceutically acceptable carrier.
 24. The methodof combatting pain and/or inflammation which comprises administering aneffective amount of the compound of claim 22 to a patient in need ofsuch treatment.